Hepatitis C virus (HCV) infection is the leading cause of liver-related morbidity and mortality in the United States, with an increasing number of deaths due to HCV-associated cirrhosis and liver cancer predicted over the next two decades. Spontaneous clearance is the best outcome of infection, but this occurs in only approximately 15-45% of patients. The goal of this project is to determine the mechanisms of effective adaptive immunity in treatment-mediated clearance of HCV infection. It seems clear that adaptive responses, particularly CD8+ cytotoxic T lymphocyte (CTL) responses, are necessary but not sufficient for HCV clearance. Subjects who respond to antiviral treatment, for example, have a higher frequency of antiviral CTL than do non-responders, but pre-existing CTL are insufficient to clear chronic HCV infection. Furthermore, in acute infection, effective CTL responses cannot be established in the absence of CD4+ T cell help. We speculate that the contributions of CD4+ T cells, interferon-a (IFNa), and ribavirin to CD8+ T cell responses are linked at the level of the antigen-presenting cell (APC). We hypothesize that IFNa and ribavirin contribute to HCV clearance in part via an influence on the quality of adaptive immune responses that is mediated by effects on APCs and cells of the innate immune system, including NK cells (evaluated in Project 1). In the experiments of this project, this hypothesis will be addressed using specimens of peripheral blood and liver biopsies from patients in a retrospective case-control study and a prospective study of response to standard-of-care treatment of HCV infection. We wish to determine whether a successful response to antiviral treatment for HCV infection is related to: (1) enhancement of the polyfunctionality and maturation phenotype of CD4'' and CD8+ T cells; (2) improved DC function and decreased induction of T regulatory mechanisms (e.g., induction of T-regs, indoleamine-2,3-dioxygenase, PD-1, etc); and/ or (3) high titers of total anti-E1/E2 antibodies or of neutralizing antibodies against HCV. Given the temporal relationship between these parameters and the response to treatment, we may be able to ascertain which are likely to be causal. Viewed in conjunction with the experiments of Project 2 (on innate immunity), we will also be able to better understand the interplay between innate and adaptive immunity in treatment response to HCV.